Blood circulates in healthy blood vessels, while always maintaining fluidity. However, in morbid states such as inflammation, injury, vascular endothelial disorders and the like, blood coagulation is proceeded by a cascade reaction wherein various coagulation factors participate and, at the final stage thereof, conversion of fibrinogen into fibrin occurs to coagulate blood. A significant example thereof is intravascular coagulation, in particular, thrombosis is a representative typical example. Fibrin deposited in a blood vessel clogs up the vessel, which occasionally causes mortal diseases such as myocardial infarction, brain infarction and the like.
It is known that there is an enzyme precursor, called plasminogen, in circulating blood and that the precursor is converted into plasmin due to restrictive decomposition by a plasminogen activator. Plasmin, which is a serine protease having affinity to fibrin, decomposes and dissolves fibrin. The series of these reactions is called a fibrinolysis reaction. A drug, which can accelerate the fibrinolysis reaction, dissolves and removes fibrin once formed, thereby effective for treatment of thrombosis and prevention of a recurrence thereof.
Hitherto, plasminogen activator preparations or protein preparations such as urokinase, tissue plasminogen activator, streptokinase, prourokinase and the like have been used as drugs which accelerate the fibrinolysis reaction by activating the enzyme precursor, plasminogen, to form plasmin [Biochim. Biophys. Acta, 24, 278 (1957); J. Biol. Chem., 256, 7035 (1981); Trends. Biochem. Sci., 4, 1 (1979); and Blood, 67, 1215 (1986)].
A pharmaceutical composition for preventing and treating thrombosis comprising as an active component retinoyl L-ascorbate (Japanese Patent Laid-Open Publication No. 66160/1988) and comprising as active components retinoic acid and L-ascorbic acid (Japanese Patent Laid-Open Publication No. 13/1987) have also been known.
Further, it has been reported that steroids such as stanozolol and the like have antithrombotic activities [Fibrinolysis, Vol. 1, pp 29-32 (1987)].
However, these known drugs have various drawbacks. For example, the enzymatic preparations such as urokinase, tissue plasminogen activator and the like have a relatively short half life in blood, so that systemic hemorrhagic trend is caused by excess administeration of said enzymatic preparations. Since streptokinase is a foreign protein derived from bacteria, it has immunogenicity. An ascorbic acid, retinoic acid and the like are required to have a high concentration for manifesting its activities. Further, steroids have strong side effects.
Thus, it is desired to develop a new drug for treating and preventing thrombosis which has improved activities with minimized side effects.